The neurovascular hypothesis states that an impaired brain-to-blood efflux of amyloid protein (ABP) at the vascular blood-brain barrier (BBB) is an important mechanism underlying ABP accumulation and cognitive impairments in patients with Alzheimer's disease (AD). Low-density lipoprotein receptor-related protein-1 (LRP) has been identified as the major efflux pump at the BBB for ABP. Zlokovic and co-workers have shown that LRP is deficient in the BBB of patients with AD and of Hsiao mice that overexpress amyloid precursor peptide (APP). We have shown that ABP efflux is impaired at the BBB in animals which overexpress ABP and that knockdown of APP expression with antisense restores BBB efflux of ABP. This suggests that ABP poisons its own transporter, LRP. Our goal is to determine whether the mechanism of impaired efflux of ABP is caused by ABP-induced oxidative damage to LRP. ABP, especially in its oligomeric form, induces oxidative stress and by this mechanism impairs the function of transporters other than LRP in non-BBB tissues. LRP in non-BBB tissues is already known to be readily oxidized and its ability to transport its other ligands in those tissues is impaired in its oxidative state. Our hypothesis is that ABP impairs its own efflux at the BBB by oxidizing LRP. We will test this hypothesis in 3 Specific Aims: Specific Aim 1: To determine in vivo whether mice that do overexpress APP have an oxidized LRP and whether ABP efflux can be restored to normal rates by treatments which reduce ABP or by antioxidants. Specific Aim 2: To determine the role of ABP and oxidation in impairing BBB efflux of ABP in vitro in a BBB monolayer model that uses brain endothelial cells derived from mice that do not overexpress APP. Specific Aim 3: To determine the status of oxidative modification of LRP in human brain tissue obtained at short post mortem intervals (PMI; specifically, < 4h after death) from patients with AD and mild cognitive impairment (MCI) relative to that from control brain tissue and correlate this information to the level and oligomeric status of ABP1-42 in those same brains and to compare this to a similar analysis for the mice that overepress APP.